P767: CLINICAL SIGNIFICANCE OF ROUTINE HIGH-RESOLUTION STRUCURAL VARIANT PROFILING IN MYELODYSPLASTIC SYNDROMES
Authors: H. Yang, G. Garcia-Manero, K. Sasaki, G. Montalban-Bravo, Z. Tang, Y. Wei, T. Kadia, K. Chien, D. Rush, H. Nguyen, A. Kalia, M. Nimmakayalu, C. Bueso-Ramos, H. Kantarjian, L. J. Medeiros, R. Luthra, R. Kanagal-Shamanna
Journal: HemaSphere (2022)

Background: Structural Variant Profiling (SVP) using high-resolution technologies, in combination with NGS-based mutation analysis, can inform critical cytogenomic data needed for improving the prognostication and outcomes in patients (pts) with MDS. Optical Genome Mapping (OGM) is a novel non-sequencing-based technique for genome-wide high-resolution SVP for all types of SVs: copy number alterations, structural rearrangements, inversions and partial tandem duplications (PTD). Aims: The goal was to evaluate the clinical implications of SVP on prognosis and risk-stratification in a large series of consecutive treatment naïve MDS pts. Methods: All patients (pts) underwent conventional chromosomal banding analysis (CBA), OGM and targeted 81-gene panel NGS. We compared the cytogenetic [based on comprehensive cytogenetic scoring system (CCSS)] and R-IPSS risk groups between data generated by CBA and OGM respectively and correlated with outcomes. For OGM, CCSS was calculated from the predicted karyotype generated by consolidatied alignment of multiple individual SVs. Results: There were 101 newly diagnosed MDS pts (71 men; 29 women). The median age was 72 (25-92). The distribution of CCSS groups [Very Good (3%), Good (43%), Intermediate (22%), Poor (10%), Very Poor (21%)] and R-IPSS risk categories [Very low (5%), low (30%), Intermediate (27%), High (17%), Very high (20%)]. Two patients had incomplete karyotype. By generating predicted karyotypes from OGM data, there were 224 clinically significant unique aberrations. Of these, 94 (40%) aberrations (seen across 34 patients) were not detected by CBA. These included SVs affecting KMT2A, MECOM, TP53, NUP98 among others. Comparison of CCSS cytogenetic groups between OGM and CBA showed that OGM data upgraded the CCSS cytogenetic-risk in 12 pts (resulting in R-IPSS upgrade in 9 pts) and downgraded in 7 pts (R-IPSS downgraded in 6 pts). Together with the results for 2 patients with non-informative karyotype, OGM modified the CCSS for 21% pts, and R-IPSS category for 17 (17%) pts. Since CCSS is influenced by the number of alterations, there were patients where OGM data, though clinically important, did not change the CCSS/R-IPSS category. To capture this, we defined an “actionable SV” as (1) prognostic, not recognized in the CCSS criteria (KMT2A-PTD, TP53 allele status) or (2) potential eligibility for a clinical trial, such as rearrangements in KMT2A, MECOM, or NUP98. Well-established SVs defined in CCSS were ignored. Based on this, 13 (13%) pts had an “actionable alteration” (9 with a positive finding). When both the CCSS change and actionable alterations were combined, OGM results provided informative data in 28 (28%) patients. Next, we evaluated the impact of CCSS-CBA and CCSS-OGM groups using outcome data. Over a median follow-up duration of 34 months, the median OS was 86 months. Using Harrell’s concordance index, OGM had a slightly improved prediction of prognosis for both CCSS [0.7 vs. 0.665] and R-IPSS categories [0.705 vs. 0.69] compared to CBA. By UVA, the following parameters associated with outcome: SF3B1 mutation [p=0.030; HR 0.343; CI 0.130-0.901], TP53 mutation [p=0.001; HR 3.232; CI 1.582-6.601], CCSS score by CBA [p=0.001; HR 1.690; CI 1.250-2.286] and CCSS by OGM [p<0.001; HR 2.051; CI 1.488-2.827]. By MVA analysis, CCSS by OGM [p<0.001; HR 1.956; CI, 1.367-2.798], but not CCSS by CBA), BM blast percentage [p=0.026; HR 1.079; CI, 1.009-1.153] and TP53 mutation [p=0.040; HR 2.335; CI, 1.038-5.250] associated with prognosis. Summary/Conclusion: High-resolution SVP by OGM improved the prognostic risk stratification in MDS.